Treatment and Prophylaxis of Nerve Agent/ Organophosphates Intoxication

Basic mechanism of action of organophosphates (OP)/nerve agents is based on acetylcholinesterase (AChE) inhibition and subsequent accumulation of neuromediator acetylcholine at the cholinergic synapses, either peripheral or central, causing cholinergic hyperstimulation and development of symptoms of poisoning, followed by metabolic dysbalance and, without eff ective prophylaxis/treatment leading to death. Th e treatment of nerve agents poisoning consists of administration of parasympatholytics (preferably atropine), cholinesterase reactivators (oximes) and anticonvulsants (usually diazepam). Th e choice of reactivators is not so simple. Th eir administration alone is not eff ective but simultaneous administration with atropine potentiates their antidotal eff ects based on AChE reactivation at the cholinergic nerve synapses. AChE reactivation at the peripheral nervous system is indisputable; however, their passing the blood-brain-barrier facilitating their central eff ect is discussed. On the basis of our own and literature data, central reactivation effi cacy of some oximes in vivo is demonstrated. Th ough the research is very intensive, unfortunately, up to now, there is not universal reactivator suffi ciently eff ective against all nerve agents/OP. A possible direction solving this problem is discussed – it is the use of combination of more reactivators. Th e good raectivating and therapeutic eff ect of combination of trimedoxime and HI-6 against tabun poisoning in rats is demonstrated. Prophylaxis against nerve agent intoxication is based on various approaches: Keeping AChE, key enzyme for toxic action of OP/nerve agents intact (protection of cholinesterases) is a basic requirement for eff ective prophylaxis. Detoxifi cation realised by administration of the enzymes splitting the OP or evaluating specifi c enzymes (cholinesterases) is another possibility (stoichiometric and catalytic scavengers). Th e antidotes currently used for the treatment of OP poisoning including reactivators are to be tested as prophylactics. Th is principle can be considered as a „treatment in advance”. Th e problem with use of reactivators is the timing, duration and achievement of suffi cient levels of these antidotes after the administration. Transdermal administration of reactivators solves these diffi culties. As a result of this research, prophylactic antidote TRANSANT (transdermal patch containing HI-6) was developed as the prophylactic mean and introduced into the Czech Armed Forces. Future development will be focused on scavengers (cholinesterases and other enzymes) acting before the binding of nerve agent to the target sites, and to other drugs either reversible cholinesterase inhibitors (e.g. huperzine A, physostigmine, acridine derivatives etc.)